The Nonartemisinin Sesquiterpene Lactones Parthenin and Parthenolide Block Plasmodium falciparum Sexual Stage Transmission

Abstract

f Parthenin and parthenolide are natural products that are closely related in structure to artemisinin, which is also a sesquiterpene lactone (SQL) and one of the most important antimalarial drugs available. Parthenin, like artemisinin, has an effect on Plasmodium blood stage development. We extended the evaluation of parthenin as a potential therapeutic for the transmissible stages of Plasmodium falciparum as it transitions between human and mosquito, with the aim of gaining potential mechanistic insight into the inhibitory activity of this compound. We posited that if parthenin targets different biological pathways in the parasite, this in turn could pave the way for the development of druggable compounds that could prevent the spread of artemisinin-resistant parasites. We examined parthenin's effect on male gamete activation and the ookinete-to-oocyst transition in the mosquito as well as on stage V gametocytes that are present in peripheral blood. Parthenin arrested parasite development for each of the stages tested. The broad inhibitory properties of parthenin on the evaluated parasite stages may suggest different mechanisms of action between parthenin and artemisinin. Parthenin's cytotoxicity notwithstanding, its demonstrated activity in this study suggests that structurally related SQLs with a better safety profile deserve further exploration. We used our battery of assays to test parthenolide, which has a more compelling safety profile. Parthenolide demonstrated activity nearly identical to that of parthenin against P. falciparum, highlighting its potential as a possible transmission-blocking drug scaffold. We discuss the context of the evidence with respect to the next steps toward expanding the current antimalarial arsenal.A n estimated 198 million cases of malaria and 584,000 deaths, mostly among young children, were reported worldwide in 2013 (1). However, as a result of concerted control efforts since 2000, including antimalarial drugs, mortality has declined by 47%, resulting in an estimated 4.3 million lives saved (1). Artemisinin, delivered with a partnered drug, is one of the fastest acting antimalarial therapies available (2, 3). However, antimalarial resistance in Plasmodium falciparum has been described recently in Southeast Asia (4). This discovery emphasizes the need for novel compounds that are effective against resistant strains, presumably because they act on the parasite differently from artemisinin. Artemisinin was originally isolated from Artemisia annua, or sweet wormwood, a member of the Asteraceae family. We hypothesized that natural product compounds derived from related family members might retain potent activities against Plasmodium while targeting different biological pathways.Parthenin is a sesquiterpene lactone (SQL) derived from Parthenium hysterophorus, which is an invasive, flowering annual weed in the Asteraceae family; it grows to 2 m in height, with small white flowers, and has spread throughout much of the world (5). P. hysterophorus causes millions of dollars in damag...

Host plant forensics and olfactory-based detection in Afro-tropical mosquito disease vectors

“…These observations strongly suggest that mosquitoes possibly pierce through plant tissue to draw nutrients from plant sap in addition to nectars. In such a scenario, the mosquitoes would be predisposed to a few plant metabolites which may impact on their fitness and pathogen transmission potential, as evidenced in previous studies [ 21 , 25 , 26 ]. Given that these Afro-tropical mosquito species can discriminate their host plants from a plethora of plant species present in their habitats, with more than one host plant identified for three of the mosquito species, it is possible that the mosquitoes forage on different host plants for different fitness-related benefits.…”

“…On the other hand, abundance of flowering plants has been linked to reduced human biting behavior by mosquito disease vectors, which can impact either positively or negatively on disease transmission potential depending on the infection status of the mosquitoes [ 13 , 20 , 23 , 24 ]. In addition, studies have shown that both mosquitoes and sandflies imbibe plant secondary metabolites during plant feeding, some of which reduce parasite load in the vector [ 21 , 25 , 26 ]. This has led to the hypothesis of possible self medication by these disease vectors [ 15 , 26 ] opening up new avenues for exploiting phytochemicals in development of novel chemotherapeutics against the pathogens they transmit.…”

“…In addition, studies have shown that both mosquitoes and sandflies imbibe plant secondary metabolites during plant feeding, some of which reduce parasite load in the vector [ 21 , 25 , 26 ]. This has led to the hypothesis of possible self medication by these disease vectors [ 15 , 26 ] opening up new avenues for exploiting phytochemicals in development of novel chemotherapeutics against the pathogens they transmit. Thus, beyond the provision of nutrients, understanding plant feeding in disease vectors offers promising opportunities for development of new control strategies against the myriad of vector borne diseases.…”

Innovative approaches to exploit host plant metabolites in malaria control

“…In additional experiments, the natural products parthenin and its analogue parthenolide, found in the plant feverfew, Tanacetum parthenium , were found to equally reduce the parasite load in An. gambiae , which was comparable to artemisinin, the main active ingredient in the current antimalarial drug . Given the fact that ethnobotanical information led to the discovery of the plants Chichona spp.…”

“…gambiae, which was comparable to artemisinin, the main active ingredient in the current antimalarial drug. 28 Given the fact that ethnobotanical information led to the discovery of the plants Chichona spp. and Artemisia annua for the treatment of malaria, it would be interesting to establish whether these plants are also fed upon by malaria mosquitoes.…”